Endogenous Regeneration Mechanisms of the Heart

Objectives

We like to advance the knowledge on endogenous regenerative capacity of the heart in response to ischemic heart disease, cancer and chemotherapy induced cardiac damage, pregnancy associated heart failure and catecholamine-induced cardiac cell death. Hereby, we focus on the cross talk among cardiac cells, the potential of secreted factors, non-coding RNAs and small molecule therapies. Moreover, we carefully analyze the regenerative potential of the adult heart with regard to the cardiac micromilieu. More recently, we embarked into preventive research using epidemiological studies to analyze the role physical exercise and of secreted factors by the gut microbiome for the regenerative potential of the cardiovascular system.

Milestones:

Understand the pathophysiology of lost regenerative capacity of the heart with regard to the microcirculation, cardiac fat deposition and comorbidities such as cancer, catecholamine stress and pregnancy stress.

Identify novel biomarkers to access the regenerative potential of the heart and identify novel therapeutic targets to improve endogenous cardiac regeneration, for example by improving the cardiac microenvironment.

Evaluate the influence of development and sex as well as genomics, proteomics and metabolomics with regard to the endogenous regeneration.

Reflect all of these in translational studies using epidemiological and clinical data from patient registries (PPCM registry) and cohort studies (Rebirth Active men and women) as well as biobank material data.

Research Focus

The regenerative capacity of an organ depends on how good its endogenous repair mechanisms function is. In the adult heart endogenous regeneration ability is in general low and consists mainly on improved vascularization and specific fibroblast phenotypes. Those are coordinated by complex inter- and intracellular signaling networks involving myocytes, endothelial cells, fibroblasts and progenitor cells. Paracrine mediators released by these cardiac cells acting locally and systemically, orchestrate endogenous healing and regeneration of the injured heart. In REBIRTH 1, we discovered several chemokines, cytokines, and growth factors (e.g., CCL2, EPO, 16kDa Prolactin) as critical paracrine modulators of cardiac healing, regeneration and remodeling. In REBIRTH 2 we discovered that specific pathomechanisms such as catecholamine stress, inflammation, cancer or sedentary lifestyle limit the regenerative capacity of the heart and of the entire cardiovascular system. We discovered that metabolic impairment and insulin signaling play crucial roles hereby. Moreover, we also discovered that specific biomarkers, for example the plasminogen activator inhibitor-1 (PAI-1) and certain microRNAs indicate the risk for disease and may serve at the same time as therapeutic targets to prevent cardiovascular damage and improve regeneration. Moreover, we discovered that the genetic background respectively mutation in cardiac genes are modulators of the regenerative capacity.

Finally, we completed investigator initiated clinical studies on peripartum cardiomyopathy proving the efficacy of adding the prolactin blocker bromocriptine to standard heart failure medication as an efficient therapy to promote healing and to prevent peripartum cardiomyopathy in patients at risk. These observations will be included this year in the new guidelines on treatment of PPCM.

Finally, from our involvement in the regenerative training strategies we learned how powerful physical exercise can enhance regenerative capacity and that factors like systemic inflammation are limiting it.

Main future aims are to investigate genetic and epigenetic risk factors and the influence of comorbidities for acute and longterm damage of the cardiovascular system. Biomarkers to predict longterm damage and small molecular approaches to improve regeneration will be developed.

Furthermore, we include the effect of comorbidities, i.e. cancer, metabolic syndrome, in our research concept. We will also analyze the role of the development stage and gender. Finally, we modify our research concepts so that our cell culture based approaches rely also on human iPSC derived cardiac cells, that we include also living human cardiac tissue slices (which we can freeze alive). We will use animal models but mainly will reflect on patient and cohort study data and biobank material.